DESCRIPTION (Adapted from Investigator's abstract) The normal immune system has the capacity to regulate T-cell function, in order to resist the effects of pathogens and yet prevent the development of pathological autoimmune responses. Clonal anergy has been proposed as one potential mechanism for this control of immune reactivity in helper T cells. Anergy is defined as a state of T-cell unresponsiveness that prevents their proliferation in response to antigen stimulation. Previous studies indicated that defective IL-2 production underlies this unresponsiveness, and this arises from a block in signal transduction to the IL-2 gene enhancer. Specifically, it has been shown that: a) transactivation at AP-1 sites fails, b) AP-1 nuclear complex formation is defective, c) c-fos, fosB, and junB expression cannot be induced, d) ERK and JNK activation are blocked, despite normal protein levels, and e) PMA activation of PKC bypasses the clonal anergy defect. Thus, a defect in signal transduction up-stream of MAPK activation at the level of coupling between the TCR/CD3 complex and p21ras appears to be the cause of clonal anergy. With this new information, this research project will target the TCR/p21ras/MAPK/AP-1 signal transduction pathway for further investigation, and define those biochemical alterations that impair the expression of the IL-2 gene.